The primary goals of this program are to gain further insight into the structure and function of neurotransmitter systems in the overall operation of the mammalian central nervous system (CNS), and the molecular mechanism of action of drugs which act on the CNS, as well as the mechanism(s) through which the immune and other peripheral systems are influenced by the CNS in normal and disease states. The multidisciplinary approach utilized in this program employs rational drug design based on structure-activity relations and molecular modeling, modern organic chemical synthesis, pharmacology, biochemistry, immunology and requires collaboration with other appropriate disciplines. Elucidation of the molecular structure and mechanism of action of the ligand-receptor systems and their antagonists provides new opportunities for the design of superior drugs and understanding disorders for which the pathogenesis is largely obscure. Synthetic programs are continuing to develop new ligands for imaging brain drug receptors by positron emission tomography (PET) and single photon emission computed tomography (SPECT) scanning. The NIH Opiate Total Synthesis continues to be employed to provide previously inaccessible unnatural enantiomers of opiates and derivatives (e.g., (+)-buprenorphine and (+)-diprenorphine) as new pharmacological agents and research tools. (+)-Buprenorphine is a potentially valuable research tool in mechanistic studies of suppression of cocaine self-administration by (-)-buprenorphine. The role of classical opiate receptors in cocaine addiction is now being intensely studied. (-)-Buprenorphine appears to protect against the lethal effects of cocaine by a process mediated by mu-opioid receptors. Oxide-bridged 5-phenylmorphans are being studied, through synthesis and computer-assisted molecular modeling, as probes for narcotic receptor mediated phenomena. Irreversible antagonists to selective opioid receptors are also under investigation. Our recently synthesized UPHIT has been found to irreversibly inhibit binding at kappa sites and may prove useful in determining the biological function of kappa receptor subtypes.